Ac020239t-Micro Total Analysis Systems. 2

Micro Total Analysis Systems. 2. AnalyticalStandard Operations and ApplicationsPierre-Alain Auroux,† Dimitri Iossifidis, Darwin R. Reyes, and Andreas Manz*

Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, U.K.

Review Contents

Analytical Standard Operations 2637Sample Preparation 2637Injection 2638Fluid and Particle Handling 2638Reactors and Mixers 2639Separation 2640Detection 2642

Applications 2644Cell Culture and Cell Handling 2644Clinical Diagnostics 2645Immunoassays 2645Proteins 2645DNA Separation and Analysis 2645Polymerase Chain Reaction 2646Sequencing 2646

Literature Cited 2647

After having reviewed some aspects of microfluidic systempreparation in the first part (1), in this second part of the reviewwe will cover a number of standard operations (namely: samplepreparation, sample injection, sample manipulation, reaction,separation, and detection) as well as some biological applicationsof micro total analysis systems (namely: cell culture, polymerasechain reaction, DNA separation, DNA sequencing, and clinicaldiagnostics). As previously, we will include papers issued fromdifferent scientific journals as well as useful abstracts from threeconference proceedings: MEMS, Transducers, and µTAS. In thissecond part, we do not include the period covered by the historysection (1975-1997) from part 1 but try to cover the relevantexamples of the literature published between January 1998 andMarch 2002. We briefly describe articles that struck us as needingspecial attention, while more “standard” papers are dutifullyreported in groups of interest. An article might be included inmore than one section, depending on the ideas developed in it.

ANALYTICAL STANDARD OPERATIONSSample Preparation. 1. Sonication. Lysis of anthrax spores

was performed by Belgrader and co-workers using a minisonicatorsystem to extract DNA, to amplify it by polymerase chain reac-tion (PCR), and to detect it in a short period. The device wascapable of performing the whole process in less than 15 min (2).A subsequent work performed by Taylor et al. using the samesonicator system studied the conditions to obtain a continuouscontact between the sonicator tip and the liquid (3). Meng et al.used an ultrasonic device to concentrate their sample, and they

reported the successful concentration and manipulation of poly-styrene spheres using acoustic radiation pressure (4). Moreliterature concerning sonication on chip is available (5).

2. Extraction. Smith’s group reported a sample cleanupmethod using microdialysis as well as an integrated microfabri-cated device for dual microdialysis: two microdialysis membraneswere sandwiched between three polymer layers containing ser-pentine channels with the fluids running in counterflow one tothe other (6, 7). Bohm et al. developed a microdialysis systemthat allowed them to perform on-line monitoring of clinicalsubstances (8). Jiang et al. performed a dialysis for affinity captureon their plastic microfluidic system by using poly(vinylidenefluoride) membranes (9).

Shaw et al. used a liquid-liquid extraction system to performmultiple parallel extractions of 10 separate organic fluids using asingle aqueous feed (10). Hibara et al. developed a liquid-liquidphase separation on chip using 2 glass substrates, one of whichhad been chemically modified (11). Hisamoto et al. developed asequential ion-sensing system, which involved the alternatingpumping of several organic phases containing a pH indicator dyeand an ion-selective neutral ionophore. The organic phase wasput in contact with the aqueous phase, forming a stable aqueous-organic layer in the microchannel where the ions were selectivelyand sequentially extracted (12). The same group also performedan ion pair extraction by a neutral ionophore-based ion (13).Minagawa et al. performed a chelation process of cobalt and asubsequent solvent extraction of the complex in a wet analysissystem (14). Tokeshi et al. improved the cobalt complex extractionsystem (15) and also developed an ion pair microextraction ofiron in chloroform by putting two parallel laminar flows of differentphases in contact (16).

Yu and co-workers prepared monolithic porous polymerswithin the microchip channels and used them to perform on-chipsolid-phase extraction and preconcentration (17). A microchip withchannels modified with C-18 was successfully used for solid-phase extraction. Samples were enriched, and subsequently, anelution of the compound was achieved by changing the aceto-nitrile concentration in the buffer (18). A microfluidic device witha bead-trapping chamber was fabricated and used with octade-cylsilane-coated silica beads for the solid-phase extraction stepwhile elution was performed by means of electroosmotic flow (19).Li et al. performed both a sample stacking and a solid-phaseextraction on their device prior to mass spectrometric detection(20). Wolfe et al. fabricated a solid-phase extraction method toisolate nucleic acids. The three-step procedure is as follows:DNA adsorption, contaminants removal, and adsorbed DNAelution (21).

† Current address: Division of Oncology, Functional Genomics Unit, Univer-sity Children’s Hospital, Zurich, Switzerland.

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10.1021/ac020239t CCC: $22.00 © 2002 American Chemical Society Analytical Chemistry, Vol. 74, No. 12, June 15, 2002 2637Published on Web 05/17/2002

Lee et al. presented an electrostatically active filter used forcollection of airborne particles (22). Weigl et al. relied on adiffusion-based mixing and extraction device to detect a singleanalyte (23). Burns and Ramshaw developed an extraction methodon-chip using slug flow (24).

3. Preconcentration. Figeys and Aebersold used computer-controlled differential electroosmotic pumping of aqueous andorganic phases to generate solvent gradients and solvent flows:they could change in situ and in real time the composition of theirsolvent/sample by ramping the concentrations of solvents A andB from proportion x and y to proportion y and x (25). Thegeneration of concentration gradients in a microfluidic networkwas performed by Jeon et al. as well as by Dertinger andco-workers: using three inlets on their device, they could generateparallel streams of solutions of different concentrations in adjacentmicrochannels and generate a gradient by combining the differentstreams in one outlet. The gradient obtained could have differentshapes depending on the design used (26, 27).

Ikuta and co-workers presented a novel microconcentrationchip using an ultrafiltration membrane. The membrane dividedthe reactor into two compartments and retained the reactivemolecules (firefly luciferase and beetle luciferinin) in the bottompart. An optical sensor monitored in real time the biochemicalluminescence of the process (28). Jemere et al. presented amicrochip structure packed with coated microspheres used forselective sample cleanup and preconcentration (29).

Kutter et al. investigated sample stacking as well as on-chipcomplexation in order to improve the sensitivity of their capillaryelectrophoresis microchip (30). Field amplification stacking wasdeveloped by Lichtenberg and co-workers as a sample precon-centration method to inject long plugs of samples. Up to 65-foldsignal enhancement was obtained, and a minimum electrophoreticdiscrimination during injection was observed (31). Palmer et al.studied the stacking conditions for neutral analytes in capillaryelectrokinetic chromatography in order to inject long sample plugswhile at the same time narrowing the analyte peak width (32).

Cabrera and Yager employed zone electrophoresis and iso-electric focusing to concentrate bacterial solutions (33). Wen etal. reported a microfabricated isoelectric focusing device andinvestigated its stability regarding electrospray ionization-massspectrometry (34). Herr et al. investigated the use of isoelectricfocusing as a mean of providing purified and concentrated samples(35).

Pickering et al. performed isotachophoresis on glass chips,integrating a laser system that would allowed them to detect thezone boundaries by measuring the laser beam deflection (36).Fielden et al. developed a miniaturized planar isotachophoresisdevice that they applied to the separation and detection (via aconductivity method) of transition metal ions (37). Baldock et al.designed a planar poly(dimethyl siloxane) device to performsample preconcentration using capillary isotachophoresis followedby conductivity detection (38). Grass et al. fabricated, by hotembossing, a PMMA device for isotachophoresis with an inte-grated conductivity detector. Separations of organic acids wereused to demonstrate the principle of the isotachophoresis chips(39). Another approach was suggested by VanderNoot et al. inwhich the isoelectric focusing was performed by using electro-kinetically generated pressure mobilization (40).

Injection. An injection system, which uses a porous membraneto electrically connect a sample reservoir with the separationchannel, was used by Khandurina and co-workers to electroki-netically concentrate DNA samples followed by the injection andelectrophoretic separation of the samples (41). Deshpande et al.studied novel designs for electrokinetic injections in a micro totalanalysis system (42). Zhang and Manz studied the influence ofcross and tee injectors having narrow sample channels andreported an improvement of resolution, column efficiency, andsensitivity (43). Greenway et al. presented a micro flow injectionsystem optimized for the determination of nitrite by a spectro-photometric detection (44).

A gated valve using a single voltage source and three reservoirswas demonstrated by Jacobson and co-workers. The systemutilized a high-voltage relay to interrupt the buffer flow and toallow the injection of a plug of sample (45). Valving characteristicswere controlled by the manipulation of the electric field strengthduring the sample loading and dispensing (46, 47). A system forcontinuous multisample injection was studied by Lee et al. Theyfirst established a theoretical model and then fabricated a matrixof flow switches comprising M inlet ports × N outlet ports on aquartz substrate (48).

Nilsson et al. presented a microdispensor with which theejected droplets were covered with a secondary layer of liquid,decreasing the contamination of the nozzle by the primary liquid(49). Attiya et al. studied different parameters in order to providean optimized interface for sample injection from the externalenvironment to microfluidic electrophoresis chips (50). O’Neillet al. presented an injection system able to deliver picoliter sampleplugs for miniaturized liquid chromatography (51). Lin et al.offered a novel approach that enables a microchip to be directlycoupled with a flow-through analyzer for uninterrupted sam-pling: as the sampling channel is kept electrically floating, thereis no need for electrical connections, thus allowing the connectionwith any pressure-driven system without further modification (52).Fang and co-workers designed a world-to-chip interfacing includ-ing a flow-through sampling reservoir featuring a guided overflowdesign (53). The reader can find more literature concerninginjection (54-56).

Fluid and Particle Handling. Jacobson et al. used a singlevoltage source to electrokinetically control their sample. Threesample reservoirs and three buffer reservoirs were present onthe device, and the electrokinetic control was used to bring thereactants to different mixing stations (57). Polson and Hayespublished a detailed study of electroosmotic flow control of fluidson a capillary electrophoresis microdevice (58). Lin and Wudeveloped an array electrode design for moving the electric fieldof capillary electrophoresis chips, thus reducing the requireddriving voltage (59). Prins et al. used the electrostatic forces onthe meniscus originating from the solid/fluid interface to controlthe fluid position in a multichannel structure (60). Moorthy et al.performed an active control of electroosmotic flow by using light.To do so, they coated the inner walls with a semiconductor (TiO2)whose surface charge changed when irradiated with UV light,modifying the ú potential and thus changing the electroosmoticflow (61). Ghosal investigated the effect that analyte adsorptionon walls had on electroosmotic flow (62). Jacobson et al. studiedelectrokinetic transport through nanometer-deep channels and

2638 Analytical Chemistry, Vol. 74, No. 12, June 15, 2002

obtained results in good agreement with theoretical predictions(63). Modulated concentrations of a dye were used by Buhler etal. to study the characteristics of laminar flow in microchannels.The process could be approximately described by simple math-ematical expressions (64). A study of gas flow in microchan-nels was performed by Lee et al. investigating the pressure lossdue to friction occurring at channel bends (65). Grant and co-workers described several new approaches regarding magneto-hydrodynamic flow control (66). The manipulation of magneticbeads in an aqueous suspension in a microchannel by usingmicrofabricated circuits was demonstrated by Deng et al. (67, 68).Monahan et al. presented a method based on atmosphericpressure reduction to remove trapped air bubbles in microchan-nels (69).

Kwok et al. presented a radiative technique used to measurethe velocity of electrokinetically driven fluorescent particles, byemploying Shah convolution Fourier transform detection (70). Anoptical approach to measure particulate flow in a microchannelusing fluorescently labeled microspheres and a focused laser beamwas presented and proved useful to measure flow rates between50 and 8 µL/min (71). Singh et al. used fluorescent liposome flowmarkers to perform microscale particle-image velocimetry (72).

Fluorescently labeled and unlabeled particles were detectedand counted by focusing the particle flow electrokinetically andthen using laser light scattering and fluorescence coincidencemeasurements (73). Voldman et al. reported the micromachiningof single-particle dielectrophoretic traps whose properties theyfound in excellent agreement with their model (74). Larsen et al.developed the “Coulter sizing” method on a chip with siliconapertures of different diameters and used their device on diaryfarms where somatic cells counts are used for quality control (75).Gawad et al. demonstrated the successful use of a micromachinedcell impedance analyzer in which counting, sizing, and populationstudies of cells, with screening rates of over 100 samples/s, wereperformed (76). Voldman et al. reported the fabrication of adielectrophoresis-based array cytometer with integrated cell trapsthat were proven to capture, hold, and selectively release multiplesingle bioparticles (77). Cui et al. used a multilayer traveling wavedielectrophoretic electrode array for manipulating particles, fluids,or both. They could detect single molecules by using either lightscattering or fluorescence emission (78). For more literature aboutisoelectric focusing, the reader is referred to Isoelectric Focusingin the section Separations.

Reactors and Mixers. 1. Micromixers. A mixer based ondiffusion was designed by Veenstra and co-workers for the mixingof a phenolic solution with water. The mixer dimensions couldbe easily adapted to match a specific time frame regarding themixing of the molecules of interest (79). Liu et al. developed athree-dimensional serpentine microchannel as a passive micro-mixer (80). Bessoth et al. fabricated a continuous-flow mixingdevice able to reach 95% of mixing completion in ∼15 ms. Thisdevice is commercially available from Upchurch Scientific (81).Floyd et al. used a chip consisting of a laminar flow mixer, a heatexchanger, and a probing region to perform infrared transmissionkinetics studies (82). Hong et al. presented a passive micromixerbased on the Coanda effect (83). The fabrication of a 100-pL mixerwas achieved by He et al. In this design, the channels parallel tothe flow were narrow whereas a larger channel ran back and forth

across the set of parallel channels at an angle of 45°. Simulationswere also performed to describe the mixing within this system(84). A mixer that used a passive method for mixing streams ofsteady flows in microchannels at low Reynolds numbers waspresented by Stroock et al. The relationship between the channellength and the Peclet number was investigated, and it was foundthat mixing could be achieved when the channel length grewlogarithmically with the Peclet number (85).

Yasuda and Ichiki designed an ultrasonic mixer where thesamples were introduced from the side wall (86). Yang and co-workers designed an active micromixer based on ultrasonicvibrations and successfully tested their microfluidic system usingwater and ethanol (87). The system was then studied further anda solution of water with uranine (sodium fluorescein salt) was usedto characterize the mixing effectiveness (88). Woias et al. reportedan active silicon micromixer whose key element is a silicon chipwith a thin piezoelectrically actuated membrane (89).

Electrokinetically driven parallel and serial mixing was dem-onstrated by Jacobson et al., using a single voltage source andchoosing the dimensions of the channels to obtain the desiredsplitting of the sample (57). Lee and co-workers developed twomixing devices, one electrokinetically driven and the other onepressure driven. The approach was based on folding and stretch-ing the material lines, leading to chaotic-like mixing (90). Lettieriet al. opposed electrokinetically and pressure-induced flows toform vortices inside microchannels of varying geometries (91, 92).Oddy et al. applied sinusoidally alternating electric fields to inducean electrokinetic instability as the mixing factor (93) and designedand fabricated micromixing devices for the stirring of fluid streamsby initiating a flow instability in electroosmotic channel flows (94).Hinsmann et al. designed and tested a micromixing device to studyrapid chemical reactions by stopped-flow resolved Fourier trans-form infrared spectroscopy. Computational simulations were inagreement with the experimental results (95).

Yang et al. reported a micromixer using turbulences producedby valveless micropumps (96). Lu et al. described the fabricationof microstirrers composed of a cap, a hub, and two rotary blades,all micromachined (97). Bohm et al. used a rapid vortex micro-mixer reactor to study high-speed chemical reactions. The reactorconsisted of 16 tangential inlets for injecting the liquid to be mixedinto a circular vortex chamber, and the velocities were highenough to induce a swirling flow field (98). Mixing geometriesused in large industrial equipment, for chemical and food process-ing, were incorporated in a micromixer using microstereolithog-raphy, a process allowing the fabrication of three-dimensionalfeatures in polymers (99). Johnson et al. presented a rapidmicrofluidic mixing device with slanted wells etched at the bottomof the channels, creating a high degree of lateral transport andrapid mixing (100).

2. Chemical Reactors. A heated chemical microreactor, madeof glass and silicon, with a heating rate of 2 °C/s was built byEijkel and co-workers and its performance investigated by thederivatization of amino acids (101). Greenway et al. used a reactorfor the determination of nitrite: it reacts with sulfanilamide toform the diazonium salt, which coupled with N-(1-naphthyl)-ethylenediamine produces an azo dye whose absorbance can bemeasured (44). Protein synthesis reactors have been presentedby Ikuta el al. as well as by Yamamoto et al. (102, 103). The use

Analytical Chemistry, Vol. 74, No. 12, June 15, 2002 2639

of quartz substrates to induce a photochemical reaction using UVlight and further detection of the products in a microreactor wasdemonstrated by Lu and co-workers (104). A nanotitrator integrat-ing electroosmotically driven nanopumps, and a sensor measuringthe potential difference between the titrant and the titrated sample,were fabricated and presented by Guenat et al. (105). Aninteresting approach where a microreactor generates compoundlibraries based on an “AND” logic operator has been presentedby Mitchell et al. (106). Mitchell et al. performed a highlyexothermic reaction on-chip, namely, the multistep reaction ofpiperidine hydrochloride with formaldehyde followed by theaddition of cyclohexyl isocyanide to give R-dialkylacetamide, andmonitored each step of the reaction using a mass spectrometer(107).

3. Enzymatic Reactors. A microreactor using enzymesimmobilized on glass beads was used by L’Hostis and co-workersto determine the concentration of glucose by enzymatic reaction(108). Tryptic digestion in a heated channel, electrophoreticseparation, and postcolumn labeling of proteins and peptides wereall integrated in a microfluidic device and its performance wasdemonstrated by Gottschlich et al. (109). The production ofelectroactive products by an enzymatic reaction (catalyzed aerobicoxidation of glucose to gluconic acid and hydrogen peroxide) andsubsequent separation and amperometric detection was carriedout in a microfluidic device by Wang and co-workers. Reactionand separation took place in the same microchannel (110). Theuse of an enzymatic reactor whose temperature is photothermallycontrolled by means of a diode laser was demonstrated by Tanakaet al. (111). They also reported the acceleration of an enzymaticreaction and preliminary kinetic studies compared to a bulk-scalereaction (112).

4. Immunoassay Reactors. Hadd et al. described flowinjection analysis, electrophoretic separation, and detection ofacetylcholinesterase inhibitors. The inhibition constants obtainedproved comparable to those obtained in conventional assays (113).A rapid diffusion competitive immunoassay based on the inter-diffusion of two fluid components and further detection down-stream was developed by Hatch et al. An analysis time of lessthan 1 min, direct analysis of blood samples, and detection in thesubnanomolar range were demonstrated (114).

Calibration standards were produced by Qiu and Harrisonwithin a microchip device using an immunoassay reaction as themodel. The mixing ratios were determined by modeling the fluidicnetwork; the mixing was performed electrokinetically (115). Amultichannel microfluidic device for immunoassays was describedby Cheng et al. This device integrated six independent mixing,reaction, and separation manifolds that worked simultaneously.A single-point fluorescent detector with a galvanoscanner was usedto acquire the data (116).

5. Postcolumn Labeling. Noncovalent postcolumn labelingof proteins, with NanoOrange dye, was achieved by Liu and co-workers by forming a fluorescent complex that was detectableby laser-induced fluorescence (117). Spikmans et al. coupled ahigh-performance liquid chromatograph to a mass spectrometerin a postcolumn derivatization step inside a micromixer (118).

Separation. 1. Chromatography. Fintschenko et al. reportedthe first use of a UV-initiated porous polymer monolith in amicrofabricated electrochromatographic separation device (119).

Oleschuk et al. prepared a packed bed for capillary electrochro-matography (CEC) separation by constructing a cavity in whichbeads coated with a stationary phase could be trapped (19).Constantin et al. reported the utilization of the sol-gel techniqueto produce self-containing open-tubular microcapillary electro-chromatography columns in a fast and easy way (120). A glasschip with polymer monolith was developed by Throckmorton etal. for reversed-phase electrochromatography (121). Electrochro-matographic separations in open channels coated with octadecyl-silane were presented by Kutter et al. Solvent programming anddifferent channel dimensions were used to evaluate the perfor-mance of this system (122). Gottschlich et al. demonstrated a two-dimensional separation using open-channel electrochromatogra-phy and capillary electrophoresis as the first and second dimensions,respectively (123). Rapid separation of peptides and amino acidsin glass microchips was performed by Singh et al. using re-versed-phase electrochromatography (124). Slentz et al. re-ported the fabrication of a poly(dimethyl siloxane) column withintegrated collocated monolith support structures that gave areproducible CEC separation over a month with a syntheticpeptide mixture (125).

He et al. reported the microfabrication of a column withintegrated collocated monolith support structures on a quartzsubstrate and compared this device with existing macroscaledevices for liquid chromatography and CEC (126, 127). Bjorkmanet al. performed capillary chromatography of proteins usingdiamond chips (128).

Desmet et al. experimentally demonstrated the possibility ofperforming shear-driven chromatographic separation; subsequentaxial sliding of these parts moved the mobile phase in the channelalong by viscous drag. The microchannels were made usingtransparencies, an ink-jet printer, and microscope slides (129).Chmela et al. addressed the issue of analytical separation of (bio)-polymers and particles by introducing a novel on-chip hydrody-namic chromatography device (130). Hydrodynamic chromatog-raphy was used by Blom et al. to separate polymer particles basedon their geometries. This separation scheme (hydrodynamicchromatography) is based on parabolic flow in which largermolecules are favored to have a higher average velocity becauseof the impossibility of approaching the wall of the channel (131,132). Wang et al. developed a high-resolution chiral separationof racemic tryptophan and thiopental mixtures using microfluidics-based membrane chromatography: the chiral stationary phaseconsisted of a porous membrane with adsorbed bovine serumalbumin (133). Seki et al. presented a pressure-driven chromato-graphic chip for separation of proteins made from poly(dimethylsiloxane) (134). Murrihy et al. presented an on-chip system forion chromatography and compared it with an open-tubular columnseparating inorganic ions (135).

A spiral-shaped separation channel of 25-cm length wasfabricated and tested for electrophoretic and micellar electrokineticchromatographic separations. Up to 21 000 plates/s were gener-ated with this high-efficiency separation microfluidic device (136).Micellar electrokinetic chromatography and high-speed open-channel electrophoresis were integrated in a single microfluidicdevice to perform a two-dimensional separation. The performanceof the device was demonstrated by Rocklin and co-workers forthe separation of peptides (137).


Hannoe et al. micromachined a separation column for anintegrated on-chip gas chromatograph. The stationary phase wasmade of amino acid films and the system tested with a methanesample (138). Lehmann et al. presented a gas chromatographydevice on which the stationary phase had been plasma polymer-ized (139). Frye-Mason et al. fabricated an on-chip gas chromato-graph and demonstrated its capability by separating a mixture ofgases such as methane, acetylene, ethane, and ethene (140).

2. Electrophoresis. An ultrafast capillary electrophoresis wasperformed by Jacobson et al. in which a two-compound mixturewas separated in 0.8 ms in a capillary length of 200 µm and afield strength of 53 kV/cm (141). Capillary electrophoresis in apoly(dimethyl siloxane) microfluidic system was reported by Duffyet al. (142). Chiral separation of extraterrestrial amino acidsextracted from the Murchison meteorite was performed in amicrofabricated electrophoresis device using laser fluorescencedetection (143). Shi et al. performed a nucleic acid analysis usinga radial 96-channel capillary electrophoresis device (144). Jeonget al. investigated a cyclic capillary electrophoresis separator ona silicon substrate (145). Morishima et al. combined both capillaryelectrophoresis and dielectrophoresis on a glass wafer to trappolystyrene beads (146). Harley et al. discussed the use of CADsoftware to design two-dimensional microchip separation devices(147). Lazar et al. presented an integrated system comprisingliquid-phase separation elements, microdigestion units, pumpingunits, and a separation channel. The device was interfaced withan electrospray mass spectrometer and the over-all performancetested with complex peptide mixtures (148). Electrophoreticseparation in a channel loop was carried out using a synchronizedcyclic electrophoresis method. Such a system is capable ofincreasing plate numbers linearly with cycle numbers (149).Capillary gel electrophoresis separation of DNA molecules of 100-1000 bp was performed using PDMS microchips, with partiallyfilled agarose gel channels (150). An analytical system thatincorporated electrophoresis and a thick-film amperometric detec-tor for the separation and detection of organophosphate neurotoxiccompounds was presented by Wang et al. (151). An integratedsystem for the detection of inorganic anions in water samples waspresented by Bodor et al. It coupled capillary zone electrophoresiswith on-line isotachophoresis sample pretreatment and a conduc-tivity detector (152). Schwarz and Hauser used capillary electro-phoresis to achieve a chiral separation of the enantiomers ofadrenaline, noradrenaline, ephedrine, and pseudoephedrine (153).A fritless separation channel on a PDMS device was packed withoctadecylsilanized-silica microspheres, and capillary electrochro-matography separation of amino acids and neutral species wasperformed (154).

Liu et al. optimized the separation matrix and temperature,the channel length and depth, the injector size, and the injectionparameters in order to perform high-speed DNA sequencing(155). Ocvirk et al. provided a detailed study of electrokineticcontrol of fluid flow in native poly(dimethyl siloxane) capillaryelectrophoresis devices (156). The properties of the electroos-motic flow in PDMS oxidized channels with low ionic strengthsolutions was studied, and a 4-fold increase in electroosmoticmobility versus native PDMS was observed (157). A study thatdemonstrated the use of low voltage in capillary electrophoresiswas presented by Lin. In this study, an arrangement of electrodes

in the separation channel was placed to create small separationzones and a voltage was applied between pairs creating zones ofa high enough electric field to separate the samples (158). Kwokand Manz reported the elimination of sample bias in CE byapplying Shah convolution differentiation Fourier transform forrear analysis (159). Ronai et al. studied the effect of operationalvariables (sieving matrix concentration, migration characteristics,separation temperature) on the separation of DNA fragments(160).

The separation of herbicides using isotachophoresis wasperformed on a glass chip and monitored using Raman spectros-copy by directly coupling the microchip to a Raman microprobe(161). The determination of metals within a device that integratedsample stacking, electrophoretic separation, derivatization, anddetection was accomplished by Kutter et al. (30). Yang and Chienapplied a new sample stacking technique based on a static stackingidea in which the microchannels were coated to eliminate theelectroosmotic flow, followed by electrophoretic separation on thesame device (162). Separation of DNA molecules based on fieldinversion electrophoresis (periodic reversion of the direction ofthe electric field) was presented by Ueda et al. In this approach,an optimized frequency produced an electrophoretic separationin a shorter effective length (163). Brahmasandra et al. offered agel-loading approach to perform gel electrophoresis using pho-topolymerized polyacrylamide gels (164).

Capillary electrophoresis has been widely applied on-chip overthe past few years and more literature is available (31, 55, 109,165-194).

3. Isoelectric Focusing. A first step in adapting capillaryisoelectric focusing to microfluidic devices was performed byHofmann et al. Using glass chips Cy-5-labeled peptides werefocused in less than 30 s (195). Isoelectric focusing was performedon quartz chip channels coated with linear polyacrylamide, andUV absorption images of the zones were produced in real time(196). A new approach for isoelectric focusing based on theformation of natural pH gradients and a model describing thephenomenon were presented by Macounova et al. (197) and laterin a more detailed study by Cabrera et al. (198). Transverseisoelectric focusing was performed in a pressure-driven flow, andoptimal conditions for the continuous fractionation of proteinmixtures were obtained (199).

4. Other Separation Methods. It is to be noted that someisotachophoresis articles can also be found under Preconcentrationin the section Sample Preparation.

Chou et al. developed an asymmetric obstacle course rectifyingthe Brownian motion, causing the molecules to be sorted by theirdiffusion coefficient (200). Edwards et al. introduced a thermalfield-flow fractionation system on-chip and its theory and testedit with an acetone sample (201). Hammond and co-workersdeveloped a device containing periodic arrays of anodes andcathodes, generating an anisotropic electric field, to trap DNAmolecules at a potential energy minimum. By switching the voltageoff, molecules were allowed to diffuse, only to be trapped in anearby potential energy minimum when the voltage was reapplied.Continuous repetition of this process resulted in the separationof DNA molecules according to their diffusion coefficients (202).Wang et al. reported a dielectrophoretic field-flow fractionationdevice tested on several cell separation problems, including the


purging of human breast cancer cell from normal cells (203). Alsobased on field-flow fractionation is the system presented by Galeet al. for blood and protein separations (204). Shinohara et al.designed a free-flow electrophoresis module with 6 inlets forbuffer, 1 inlet for sample, and 30 outlets for collection of separatedfractions (205). An entropic trap array was developed by Han andCraighead to separate DNA molecules according to size: thechannel comprises narrow constrictions and wider regions thatcause size-dependent trapping (206). Holmes et al. developed adielectrophoretic separation system in order to isolate raremolecules from a complex sample (207). Vykoukal et al. combineddielectrophoresis with field-flow fractionation and applied theirdevice to biomedical separation and analysis (208). Arai el al.presented a high-speed separation system using a laser trap anddielectrophoresis that they applied to arbitrarily selected singlemicrobes (209). Gaudioso et al. reported the micromachining ofa diffusion-based separation device. On this chip, numerous wellswere incorporated along the separation channel and are morelikely to trap the smaller, and thus faster diffusing, molecules,consequently retarding them relative to the slower diffusingproteins (210). Edwards et al. developed a microfabricated thermalfield-flow fractionation system with characteristics comparable tomacrosystems (211).

Detection. 1. Chemiluminescence and Electrochemilu-minescence. A microsystem that combines both the electrodetransducer and the photodetector for electrochemiluminiscencewas fabricated by Fiaccabrino and co-workers. The influence ofthe pH as well as the distance between the interdigitated arrayelectrodes on the luminiscence was investigated using as modelsystem a ruthenium complex and tripropylamine (212). Electro-chemiluminiscence detection was used by L’Hostis et al. todetermine the concentration of glucose after an enzymatic reac-tion, and also for the determination of codeine, without pretreat-ment, in pharmaceutical samples (108). Arora et al. presented awireless electrochemiluminiscence detector that they applied toa micellar electrokinetic chromatographic separation. They useda U-shaped floating electrode (the electrode is not connected toany external electric circuit) for the redox reaction and succeededin performing indirect ECL flow cell detection of amino acids(213). The same group had previously achieved a detection limitas low as 0.5 pM for tris(2.2′-bipyridyl)ruthenium(II) using a flowcell for ECL detection (214). DNA molecules immobilized to glassmicrochannels were hybridized and detected via enzyme-catalyzedchemilumiscence reactions, and the sensitivity and dynamic rangeof the method were determined (215). Xu et al. performed anon-line monitoring of chromium(III) by using chemiluminescencegenerated in a micromixer (216).

2. Electrochemical Detection. Woolley et al. fabricated anamperometric detector system on glass substrates and tested itfor the determination of neurotransmitters. The device alsoperformed indirect detection of DNA restriction fragments andPCR products after an electrophoretic separation (217). A screen-printed carbon electrode perpendicular to the flow direction ofan electrophoretic separation channel was fabricated, and thefactors that affected the efficiency of separation and the ampero-metric signal were appraised (218). Gold electrodes were sput-tered directly into the separation microchannel of a microfluidicdevice to operate as a working electrode of an amperometric

detection system (219). Systems that combined precolumn reac-tions, electrophoretic separation, and amperometric detection wereshown by Wang et al. to be suitable for both amino acid andenzymatic analysis. Oxidase and dehydrogenase reactions werecarried out, and the products of both reactions were simulta-neously detected showing the feasibility of a multienzyme assayon-chip (191, 220). Gawron et al. presented the first carbon-baseddual-electrode detector for microchip capillary electrophoresis: theamperometric detection was performed in either a three-electrode(single-electrode detection) or a four-electrode (dual-electrodedetection) format (221). Chen et al. presented a palladium filmdecoupler that allows the separation of the electrical system ofthe electrochemical detection from that of the electrophoreticseparation when using amperometric detection in electrophoresischips (222). Wang et al. described a novel approach generatingtwo electrophoretic peaks for a single analyte using amperometricdetection (223).

Laugere et al. studied the characteristics of a conventionalconductivity detector and then considered the downscaling aspectsto perform conductivity detection on a capillary electrophoresischip (224). Darling et al. compared conductivity and anodicstripping voltametry, using three different device types withvarying electrode distances (225). Weber et al. performed capillaryelectrophoresis with direct and contactless conductivity detectionon a PMMA device (226), and Lichtenberg et al. optimized theoperating parameters for a glass-based microchip for CE with anintegrated conductivity detector (227, 228). Guijt et al. tested theperformance of powder-blasted devices by performing the separa-tion of lithium, sodium, and potassium ions, followed by conduc-tivity detection (190). Using carbon microband electrodes, Rossieret al. fabricated an electrochemical detector on which theysuccessfully performed cyclic voltammetry (229).

An integrated potentiometric detector based on a solventpolymeric membrane has been described by Tantra and Manz(230). Wang et al. presented a glass device that integratedchemical derivatization reactions of amino acids with electroactivespecies with separation and electrochemical detection (191).Electrochemical detection in a PDMS chip using a dual-electrodearray was presented by Martin and co-workers. The arrangementof two electrodes in series allowed the detection of chemicallyreversible redox species and the identification of unresolved peaks(174). Martin et al. also developed a new electrode configurationapplied to capillary electrophoresis and electrochemical detec-tion: by using an electrically isolated potentiostat, they could placethe working electrode in the separation channel and compare itsperformance to the more traditional end-channel approach (231).

3. Fluorescence. Roulet et al. presented an array of micro-lenses to perform on-chip fluorescence detection (232). Weigl etal. used a reference solution directly present in the device’schannel to quantitatively detect clinical substances (23). Multi-channel laser-induced fluorescence detection was carried out byusing an acoustooptical deflector to move the laser between theparallel channels. Important features of this approach are theabsence of moving parts and fast-scan frequencies (233). Cross-correlation electrophoresis was employed, along with fluorescencedetection, to resolve and detect a mixture of dyes that could notbe detected in conventional ways (234). Liu et al. used afluorogenic dye that binds reversibly with hydrophobic protein


regions in order to form highly fluorescent complexes; detectionlimits as low as 0.5 pg of injected sample were achieved (117).Zugel et al. demonstrated the successful use of two-photon-excitation fluorescence detection by measuring the product of aclinically significant tissue enzyme in an electrophoreticallymediated microanalysis. The microanalysis is based on the mixingof the reactants due to their differences in mobility. When theslower reactant is injected first the faster reactant will overtakeit, mixing with it at the same time (235). The use of a microava-lanche photodiode detector embedded in a PDMS microfluidicdevice, along with an optical fiber for the excitation of fluorescentspecies, was demonstrated by Chabinyc and co-workers. The needof collection optics was eliminated as the size of the detector wascomparable with the width of the channel (236). Using a lampand a photomultiplier tube on a moving stage, scanning fluorescentdetection used for isoelectric focusing analysis in plastic micro-chips was developed (237).

Indirect fluorescence detection of a set of amino acids wasperformed by using fluorescein as the background and avoidingthe need for derivatization of samples (238). Simpson et al.reported the fabrication of a DNA analysis system allowingsimultaneous detection of various samples (239). By using indirectfluorescence detection, Sirichai and de Mello were able to achievequality control of a film-processing solution (240). Schilling et al.characterized a fluorogenic enzyme assay for the detection of celllysis products and proteins (241). Flow cytometry of Escherichiacoli, in poly(dimethylacrylamide)-coated channels, was performedby transporting and focusing the cells electrophoretically anddetecting them using coincident light scattering and fluorescence(242). Jin et al. used a dynamic labeling method for the detectionof protein-SDS complexes. They incorporated a fluorescent dyein the buffer, which interacted hydrophobically with complexes,allowing detection by laser-induced fluorescence (192). Berti etal. reported that the use of energy-transfer dye-labeled primerssignificantly improved DNA fluorescent detection (243). Maimset al. used a grating waveguide for optical analysis enablingfluorescence and absorption measurements to be undertaken on-line in microchips (244).

Wang and Morris applied analyte velocity modulation to rejectfluorescence background in plastic devices. To do so, they useda driving voltage modulated at low frequency (∼20 Hz). Theconsequence was that migration velocities were modulated at thesame frequency whereas the inherent microchip fluorescence wasnot, thus allowing the two signals to be separated by a synchro-nous demodulation (245). The diffusion coefficient of proteins andsmall molecules was studied in the T-sensor, using conventionalepifluorescence microscopy (246). Ocvirk et al. showed the useof confocal epifluorescence detection to obtain detection limitsbetween 0.3 and 1 pM. A focused laser spot of ∼12 µm in diameterwas obtained and allowed the detection of an average of 570molecules (247).

4. Nonfluorescence Optical Measurements. A detectionbased on holographic refractive index was used, along with a cyclicsquare separation channel, to follow the separation of carbohy-drates, demonstrating the potential of this approach as a uni-versal detection system for microfluidic systems (248). Kameokaand Craighead developed a nanorefractive index sensor usingphoton tunneling (249). Hosokawa presented a novel optical

method to determine local pressure using a deformable diffrac-tion grating (250). A module that coupled a fiber-optic reflec-tion probe and a small-volume silicon flow cell was used forreflection-absorption measurements. The fiber optic includedone emitting fiber and six receiving fibers and was used for op-tical monitoring of biological fluids (251). Mao and Pawlizyndeveloped an isoelectric focusing method on a quartz chip coupledto UV absorption imaging detection (196). Nishimoto et al.incorporated an optical slit for UV absorption detection on amicrofabricated CE chip (252). Jackman et al. reported twodifferent devices to perform in situ UV-visible detection and IRspectroscopy (253). On-line UV detection in microfabricatedreactors allowed Lu et al. to study the pinacol formation reactionof benzophone in 2-propanol (104). Mogensen et al. used mono-lithically integrated optical waveguides to perform UV absorbancedetection (254). A CE microfluidic device in which enhancedabsorbance detection was achieved by means of a multireflectioncell was fabricated and tested. The effective optical path lengthin this device ranged from 50 to 272 µm corresponding to 5-10-fold enhancement when compared to single-pass devices (255).The integration of an evanescent wave optical sensor for visibleabsorption measurements in optical cells of small cross-sectionaldimensions was demonstrated by Pandraud and co-workers (256).

Soughayer et al. developed and characterized cellular optopo-ration (a method that consists of rendering a cell membranetemporarily permeable so that some molecules can be incorpo-rated or extracted into/from the cells) with visible wavelengthsusing standard glass cover slips as adsorptive media (257).Reichert et al. used a nanobead-labeling method in order to detectDNA hybridization (258). Reshni et al. proposed an on-linedetection by Raman spectroscopy of an electrophoretic separationon-chip (259). Time-resolved resonance Raman spectroscopy, inmicrofluidic device flow, was used by Pan and Mathies to elucidatethe structure of a chromophore and changes in protein-chro-mophore interactions (260). After having separated seven transi-tion metal ions, Lu and Collins demonstrated the detection of the4-(2-pyridylazo)resorcinol metal chelates by using a diode and aminiaturized photomultiplier tube (261). Mizukami and co-workersused a novel microfabrication technique, “stereolithography withdouble controlled surface”, to make a chip with a photosensorarray. The device was tested with a Blue Dextran samplemeasuring the absorbance with distilled water as the reference(262). Furuki et al. presented a surface plasmon resonancedetector utilizing microfabricated channels that they applied tothe study of protein adsorption onto chemically modified goldsurfaces (263). A theoretical understanding of surface plasmonresonance sensors has been presented by Kurihara and Suzuki(264). Miclea et al. presented a microchip capable of being asource for analytical spectrometry. The device could dissociatemolecular species due to the presence of a dielectric barrierdischarge plasma. It was used in plasma modulation diode laserabsorption spectrometry (265).

5. Mass Spectrometry. Different microfabricated deviceshave been reported by Li and co-workers as well as by Zhang etal. for coupling capillary electrophoresis to an electrospray massspectrometer; they were applied to the analysis of proteolyticdigests as well as peptides (266, 267). Ayliffe et al. reported theuse of microelectric impedance spectroscopy for the electrophysi-


ological characterization of cells (268). Two mass spectrometeranalyzers, a triple quadrupole and time of flight, were connectedseparately to microfluidic devices through nanoelectrospray emit-ters to perform trace analysis of membrane proteins (269) andcarnitines in human urine (270). A device that integrated thesynthesis of compound libraries via an “AND” logic operator anda detection mode that relied on time-of-flight mass spectrometrywas presented (106). This system also allowed the parallelprocessing, in real time, of multicomponent reaction subreactions.A modular microsystem including an autosampler, microfluidicseparation device, and interface for nanoelectrospray mass spec-trometry was presented (271). Such a system was able to performsequential injections and separations of up to 30 samples/h. Denget al. used a chip-based CE/MS system to make quantitativedeterminations of drugs in human plasma (272). Wang and co-workers achieved a 15-amol sample detection limit by coupling achip and a mass spectrometer (273).

6. Other Detection Methods. A miniaturized time-scanningFourier transform spectrometer based on silicon technology hasbeen presented by Manzardo et al. showing a resolution of 6 nmat a wavelength of 633 nm after optimization (274). Fuller et al.developed a multifrequency particle impedance characterizationsystem allowing impedance measurements at three or morefrequencies simultaneously (275). Gawad et al. introduced animpedance spectrometer for cell analysis in microchannels (276,277).

A molecular emission detector employing a direct currentmicroplasma has been reported by Eijkel et al. The device employsdirect current helium plasma for molecular fragmentation andexcitation (278). Eijkel et al. also reported an atmosphericpressure dc glow discharge and its use as a molecular emissiondetector. Methane was detected with a detection limit of 2 × 10-14

g/s and a linear dynamic range of two decades (279). Atomicemission spectrometry using a microwave-induced plasma (280),a capacitively coupled microplasma (281), and a pulsed plasmasource was also reported (282); absorption spectrometry using adielectric barrier discharge and a diode laser was also reported(283). Jenkins and Manz used a micromachined dc glow-dischargedevice at atmospheric pressure for the optical detection of metalions in water (284).

Zimmermann et al. manufactured micromachined flame ana-lyzers for atomic emission flame spectrometry and flame ionizationdetection (285-287). A microfluidic device that used oligonucle-otide-tagged liposomes as hybridization markers in a sandwich-hybridization assay for RNA sensing was presented by Esch etal. (288). Veenstra et al. compared two different systems for theµ-FIA ammonium detection (289). Jackman et al. reported theintegration of multiple internal reflection (MIR) infrared spectros-copy with microreactors. These devices incorporated crystalssuitable for MIR IR spectroscopy and were used for kinetic studiesof the hydrolysis of ethyl acetate (290). Massin et al. performedon-chip NMR spectroscopy and detected concentrations of a fewpercent ethanol in water by 1H NMR in a 30-nL volume with onlythree scans (291, 292).

7. Single-Molecule Detection. Analysis of single moleculeswas performed by Fister and co-workers by focusing a laser beamin an area of a few micrometers and counting the fluorescent burstfrom each molecule. Detection limits in the picomolar range were

obtained (170). Also utilizing a fluorescence burst countingtechnique, single DNA molecules were detected by Haab andMathies. They used a cross-shape intersection to create a sheathflow, narrow the sample flow, and subsequently lead the samplethrough the focused laser beam. The device sensitivity wasimproved by such an arrangement (293). A single nonfluorescentmolecule detection method based on the thermal lens effect wassuccessfully demonstrated. Using photothermal spectroscopy, theheat produced by the relaxation process after light absorption wasmeasured (294). Using the same principle, Sato et al. reporteddetection in the subzeptomole range in glass devices (295) andTokeshi et al. measured the photothermal signal at a subsinglemolecule level expressed as expected molecule number (296).Chou et al. compared different devices for biomolecules sortingsuch as a single-molecule mapping device using near-field optics(297). Turner et al. developed optical waveguides to confine theexcitation volume in single-molecule fluorescence detection(298). Kurosawa and co-workers established a novel method forsingle-molecule DNA analysis based on physical molecularanalysis. The device consisted of a glass substrate with a sac-rificial layer and a pair of electrodes on which the DNA solutionis fed. Applying high-frequency voltage stretches and aligns theDNA molecule. A portion of the DNA molecule can then be cutoff with an AFM tip as a knife, and the sacrificial layer is dissolved.The DNA fragments are recovered by filtration and amplified bypolymerase chain reaction (299). Cui et al. presented an opticalparticle detection integrated in a dielectrophoretic device (78).More literature concerning chemiluminescence (54, 300), opticaldetection (44, 246, 301-306), electrochemical detection (51, 55,152, 153, 307, 308), mass spectrometer coupling (7, 107, 271),or more exotic methods of detection (159, 309) can be found.

APPLICATIONSThe vast majority of research work on microfluidic devices has

been directed toward the biological and life sciences. This sectioncovers papers dealing with analytical methodology for the han-dling, separation, and detection of biological moieties on-chip. Arecent review on applications for microfluidic devices, coveringthe analysis of drugs, explosives residues, enzymes, antibodies,peptides, DNA, and other biological samples, is referred to formore examples on this topic (310).

Cell Culture and Cell Handling. Red blood cells, variouspopulations of white blood cells, and platelets were differentiatedand counted using a microfluidic structure that incorporatedhydrodynamic focusing (311). Cytomechanical studies of red cellmembrane viscoelastic behavior during flow were performed ina microfluidic device that matched the limitations of cell fragility,sedimentation, and separation effects (312). The interaction ofleukocytes with their physical environment was demonstratedusing physiological flow conditions and an array of microchannelswith length in the range of human capillaries (313). Sorting ofparamagnetic particles from nonmagnetic and fluorescent particlesfrom nonfluorescent ones was achieved by Telleman et al. as apreliminary work to cell sorting (314).

The growth of E. coli expressing green fluorescent protein wasachieved in gas-permeable PDMS microfluidic devices, and theincubation process was optically monitored by fluorescence forup to a 5-h period (315). Cellular optoporation was characterized


using visible laser light and tested in microfluidic systems byloading cells, attached to microchannel surfaces, with a fluoro-phore (257). Cellular calcium flux was used to screen for agonistsand antagonists for G-protein in cultured cells (316).

Inoue et al. presented an on-chip cell culture system thatconsisted of an array of chambers in which a single cell or groupof cells was isolated from the external environment by means ofa permeable membrane. The medium was easily exchanged, andthe size of the chamber was flexible (317). A disposable microfluorescence-activated cell sorter (µFACS) was developed andused to separate E. coli cells expressing green fluorescent proteinsfrom nonfluorescent E. coli cells (318). A single microbe wasarbitrarily separated, among a large number of microbes insolution, by means of a laser-trapping force and a dielectrophoreticforce. The separation procedure took less than 20 s and could beuseful for pure cultivation of cells (209). Cabrera and Yagerpresented a method to concentrate bacterial solutions using zoneelectrophoresis and isoelectric focusing in carrier-free solutions(33). An electroporation microchip that enclosed two thin filmgold electrodes in PMMA was fabricated and tested for continuousgene transfection using Huh-7 cell lines (319). Mammalian cellswere cultured in microchambers created by using patterned flowsof etching solutions in PDMS microfluidic devices (320). A PDMSmicrofluidic device consisting of an array of microinjectors and abase-flow channel was tested for cell culture using neuronal cellspatterned in a linear fashion (321). A commercial product for cell-based assays is available from Caliper and Agilent.

Clinical Diagnostics. Common mutations in breast cancer-susceptible genes were screened by a single-strand conformationpolymorphism analysis, using polymer-coated capillary electro-phoresis and microchip electrophoresis (177). The analysis ofurine samples with high levels of amino acids as indicative ofamino acid metabolism disorders and kidney malfunction wasperformed using electrophoretic separation with indirect fluores-cence detection in a microfluidic device (238). A microfluidicdevice for clinical diagnostics based on a sandwich immunoassaysystem that used three antibodies and a thermal lens microscopefor detection was presented by Sato et al. (322). A biocompatiblepolymer was used to coat a microchannel in a quartz chip in orderto suppress the adsorption of proteins from blood serum samples.An electroosmotic pump was arranged downstream of the micro-capillary to allow the injection of the serum (323). Carnitines andacylcarnitines from standard solutions and human urine weredetermined on-chip by using capillary electrophoresis and massspectrometry (272). The concentration of oxalate, from a urinesample, was determined using a PMMA microchip coupled to apair of conductivity detectors. Detection of concentrations of 80nM was achieved (324). The determination of homocysteine andreduced glutathione (in human plasma) was achieved, by Pasaset al., using capillary electrophoresis on-chip and electrochemicaldetection (325). Fanguy and Henry determined uric acid in urineby means of capillary electrophoresis and electrochemical detec-tion. Separation of the sample in less than 30 s and a limit ofdetection of 1 µM were obtained (326).

Immunoassays. A competitive assay that allowed the mea-surement of small molecules down to nanomolar concentrationswas presented and compared with a fluorescence polarizationimmunoassay (114). Immunoreagents were immobilized directly

onto the channel walls of a microchip, and the system was testedusing protein A for rabbit immunoglobulin G (rIgG) as theimmobilized species and rIgG as sample (327). Yang et al.presented an immunoassay based on solid supported lipid bilayers,in which bilayers coating the surface of PDMS microchannelscontained dinitrophenyl (DNP)-conjugated lipids for binding withbivalent anti-DNP antibodies (328). A biopassivation procedureenabled the immobilization of antibody and subsequent immu-noreaction, using biotinylated IgG, neutravidin, and a biotinylatedreagent, to perform affinity binding assays (329). Sato et al.presented a multiple-sample bead-bed immunoassay system. Themultichannel system was capable of processing four samples atthe same time with one pump unit and completed the assay in 50min (330). A heterogeneous competitive immunoassay of humanIgG, utilizing Cy5-human IgG as tracer and Cy3-mouse IgG asinternal standard, was developed by Linder et al. in PDMS/glassdevices (331). Locascio et al. presented a bioassay based on anantibody conjugate affinity approach that used liposomes encap-sulating carboxyfluorescein molecules to amplify the fluorescentoutput signal. Competitive assays were carried out within shortincubation times due to the high fluorescent output associatedwith the liposomes (332). The reader is referred to EnzymaticReactors under the Reactors and Mixers section for moreliterature regarding immunoassays.

Proteins. The chiral separation of amino acids extractedfrom the Murchison meteorite was performed on capillary mi-crochannels to investigate the possibility of the use of micro-fluidic devices to analyze signs of extinct or extant extraterrestriallife (143). A protein-sizing method that incorporated SDS-PAGEgels with the high speed of microchip separations was presentedby Bousse (333). Continuous fractionation and separation ofproteins was carried out by a combination of transverse isoelectricfocusing and pressure-driven flow (199). Protein separation oflysozyme, cytochrome c, RNase, and fluorescein-labeled goat anti-human IgG Fab fragment was achieved using fused-silica capil-laries and glass microchips coated with thermally pyrolyzed PDMS(334).

Model proteins (R-lactalbumin, â-lactoglobulin A, â-lactoglo-bulin B) were separated electrophoretically and detected bynoncovalent postcolumn labeling (117). A dynamic labelingprocess during electrophoretic separation was used for thedetection of proteins in capillary and microchip devices (192).

Rapid on-chip protein digestion analysis using a microchipcoupled to a nanoelectrospray-mass spectrometer was demon-strated by the analysis of human hemoglobin (335). An oxidizedinsulin B chain was tryptic digested under stopped-flow conditionsin a microchip, and the products were separated within the samemicrochip device (109). Trace analysis of digested proteins wasperformed by coupling a quadrupole time-of-flight mass spectrom-eter to microfabricated devices (169). Analysis and identificationof proteins using electrospray and mass spectrometry, tandemmass spectrometry, and triple quadrupole mass spectrometry waswidely and successfully used (269, 336-338). There is onecommercial product by Caliper/Agilent for protein separations(SDS-PAGE).

DNA Separation and Analysis. A parallel design for DNAseparation based on a 96-capillary electrophoresis array wasfabricated and tested by Shi et al. The analysis of 96 alleles in


parallel was achieved, demonstrating the feasibility of performinghigh-throughput genotyping separation with this device (144). Asystem utilizing a capillary electrophoresis array, using PMMAsubstrate, was developed for ultrafast DNA separation and analysisby imaging of the bands (173).

Parameters such as DNA length, buffer additives and pH,sample salt effect, and temperature of separation were used toexplore the potential use of microfluidic devices for the detectionof deletion, insertion, and substitution mutations by heteroduplexanalysis (339). A separation microchannel of 6-mm length and alaser-induced fluorescence detection system were used to separateand detect a triplet repeat DNA fragment and DNA molecularmarker. Microchip separation proved to be at least 18 times fasterwhen compared with a conventional capillary electrophoresissystem (178). A disposable glass microchip was developed andtested for the analysis of PCR products, sizing of plasmid digests,and detection point mutation using restriction fragment lengthpolymorphism mapping (340). Other works comprising DNAelectrophoretic sizing as part of the DNA analysis were presented(239, 341).

A work in which, after PCR, allele-specific products weregenerated, separated, and typed was presented by Medintz et al.The potential of this device using a capillary electrophoresisarray coupled with a laser-excited rotary scanning confocaldetection for high-throughput single-nucleotide polymorphismwas demonstrated (166). Other allele-specific amplifications(AS-PCR) with heteroduplex analysis (176) using microchipelectrophoresis and AS-PCR for high-throughput single-nucleo-tide polymorphism using a capillary electrophoresis array (342)were described. A filter chamber array in a microfluidic devicewas used for the analysis of single-nucleotide polymorphismby using pyrosequencing, a sequencing-by-synthesis techniquethat relies on the detection of pyrophosphate, which is releasedonce a nucleotide is incorporated (343). Fast- and high-resolutionDNA separations were carried out by concentrating the DNAsamples at the entrance of microfabricated hexagonal arrays andfurther separation by pulsed field electrophoresis (344). Polycar-bonate was used as substrate for the microfabrication of a devicedesigned for PCR and DNA separation using capillary electro-phoresis (171).

High-throughput DNA separation utilizing capillary arrayelectrophoresis was carried out for genetic analysis (345-347).The use of a microfluidic electrophoretic device for rapid analysisin genotyping was presented by Barta et al. (348). Separations ofDNA introducing new types of electrophoretic separations, detec-tion modes, sample pretreatment, autosampling, and geneticanalysis were presented by several research groups (2, 41, 150,158, 163, 217, 293, 349-351). Using a system capable ofrepetitive operation, multiplexed short tandem repeats wereanalyzed by the simultaneous detection of three- and four-colormultiplexed polymerase chain reaction samples (352). There areseveral commercial products available for DNA and RNA separa-tions by Caliper, Agilent, Shimadzu, and Hitachi.

Polymerase Chain Reaction. A PCR device that incorporatedcell lysis, PCR amplification, and electrophoretic separation of thePCR products was presented by Waters et al. By thermally cyclingthe whole device to lyse the cells and to amplify the DNA, genomicand plasmid DNA were amplified and separated (341). In a

subsequent work, multiple PCRs were carried out on a microchipdevice and the separation of the products was achieved individuallyor together in the same microchip (353). In a two-step PCR,degenerate oligonucleotide primed-polymerase chain reaction wasfirst carried out in a silicon-glass chip followed by another PCRfor specific gene exons to detect deletions causing a type ofmuscular dystrophy (354). A battery-powered miniature thermalcycling apparatus for real-time PCR assay was presented and laterimproved for fast distinguishing of single-base polymorphisms(355, 356). Nucleotide differences in viral and human genomicDNA were identified using this apparatus.

A rapid PCR system that integrated a compact thermal cyclingelement that allowed fast cycles of 1 min and efficient DNAamplification with electrophoretic sizing and detection was pre-sented by Khandurina et al. Analysis times of no more than 20min were obtained (357). Thermal cycles as fast as 30 s wereobtained with a monolithic device that integrated loading, PCRamplification, and separation of a few hundred nanoliters of DNA(358). Two microdevices for PCR reaction, one incorporating fiberoptics for excitation and collection of the emitted light, and asecond using a photodiode for collection of the emitted light, weredesigned and tested (302). PCR coupled with capillary electro-phoresis was used to demonstrate the potential of a microfluidicdevice for analyzing polymorphic alleles (359).

Belgrader et al. developed a portable real-time PCR device,consisting of two independent reaction modules that alloweddifferent temperature profiles and integrated optics for four-colorfluorescence detection (360). Amplification of single DNA mol-ecule templates was performed by Lagaly et al., demonstratingthe most sensitive PCR yet obtained in a microchip device(349). Infrared was used for PCR amplification in polyimidemicrofabricated devices allowing the production of sufficientamounts of PCR products in only 15 cycles and a total amplifi-cation time of 240 s (361). A flow-through thermocycler for PCRin a silicon and glass chip was presented and its capability forhigh throughput of samples demonstrated (362). Human genomicDNA was amplified directly from cheek cells using a fullyintegrated and automated microchip capillary-based system (363).The use of additives for dynamic coating or adsorption onto glasssurfaces was studied and tested for PCR amplification of DNA(364).

Sequencing. A theoretical model and its experimental evalu-ation were demonstrated for the sequencing of DNA in micro-fabricated devices that used sieving matrixes for the separa-tion of single-stranded DNA (365). An optimization study for theuse of microchannels to perform DNA sequencing separations ofup to 500 bp with 99% of accuracy in less than 20 min wasperformed by Liu et al. Features such as separation matrix,temperature, channel dimensions, and injection were the scopeof this study (155). An independent work also reported theoptimization of capillary electrophoresis parameters for thesequencing of DNA, separating 565 bases with 99% accuracy inless than 25 min (366). Longer capillary channels were incorpo-rated in a microfluidic device and read lengths of up to 640 baseswere obtained in 150 min (367). A 16-channel electrophoresisarray was presented by Liu et al., in which parallel DNAsequencing separation of 450 bases in 15 min was performed withan accuracy of 99% (368).


A polymeric reactor device, which utilized volumes in the orderof nano- and subnanoliters, was employed to carry out sequencingreactions and polymerase chain reactions. The system reducedthe volume by a 300-fold when compared with typical Sangerchain-termination protocols (187). An optimization study of high-performance DNA sequencing on short microchannels that usedreplaceable linear poly(acrylamide) was performed by Salas-Solanoet al (369). DNA sequencing was accomplished with a systemthat used a sieving matrix and an imaging detection mode (239).High speed, high-resolution separations of double- and single-stranded DNA in plastic microfluidic systems for sequencing ofup to 700 single-stranded DNA fragments in 40 min were reportedby Boone and Hooper (370).

A significant achievement in sequencing was demonstratedby Koutny et al. when using microchannels of 40 cm long; a readlength of 800 bases with a 98% accuracy was obtained in 80 min(371). Paegel et al. presented a high-throughput sequencingmicrofabricated capillary array electrophoresis (µCAE) device,which consisted of 96 channels grouped in a radial conformation.The µCAE demonstrated a sequencing rate of 1.7 kbp/min whichis a 5-fold increase over the commercial apparatus (372).

This concludes our review of micro total analysis systems. Wehope this selection of publications is useful to the student ofthis interesting area. It should be clear however, that a more in-depth review of a narrower field will always be necessary to pre-cede any new and original research publication. We did notintend to replace that task, but hoped to provide a useful startingpoint.

“ΠΑ ΒΩ ΚΑΙ ΚΙΝΩ ΤΑΝ ΓΑΝ” “Give me a place to stand,and I will move the earth” (Archimedes 287-212 B.C.).

ACKNOWLEDGMENTThe authors acknowledge Jan Eijkel and Jennifer Auroux for

proofreading the manuscript and for their valuable suggestions andLymarie Maldonado-Baez for proof reading and discussions on thebiochemical topics. D.R.R. acknowledges National Science Foundation(Grant INT-0000462) for financial support. D.I. acknowledges Delta-Dot Limited for the financial support. P.-A.A. acknowledges SchweizerForschungsstiftung Kind und Krebs for financial support.

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Pierre-Alain Auroux studied in Strasbourg, France, at the EuropeanSchool of Chemistry, Polymers and Functional Materials (ECPM) wherehe got his M.Sc. in 2000. As part of his master’s project, he spent fourteenmonths at Orion Research, Inc. (Beverly, MA), where he helped developingelectrochemical devices for Mars soil analysis. He also went to Los AlamosNational Laboratory (Los Alamos, NM) for four months and elaborateda protocol for capillary electrophoresis analysis of dyes, interfaced withRaman spectroscopy. After graduating, he spent a year and a half inProfessor Manz′s group familiarizing himself-with microscale-fabricationtechniques. He is currently at the Children′s Hospital of Zurich (Zurich,Switzerland) working on his Ph.D.

Darwin R. Reyes is a National Science Foundation Postdoctoral Fellowat Imperial College, London, U.K. He received his B.S. in chemistry fromthe University of Puerto Rico and after working for two years in SmithKlineBeecham Pharmaceutical (Cidra, P. R.) he undertook his Ph.D. studieswith Professor Osvaldo Rosario at the University of Puerto Rico. His thesisinvolved the chemical characterization of airborne particulate matterdirected by cell-based toxicological bioassays. He has been working withProfessor Manz since 2000 developing isoelectric focusing and otherseparation modes in microfluidic devices in order to develop two-dimensional separation systems on chip.

Dimitri Iossifidis received his B.Sc. in chemistry from ReadingUniversity in 1999 and his M.Sc. from Imperial College in 2000. He iscurrently pursuing a Ph.D. at Imperial College under the supervision ofProfessor Andreas Manz. His research interests lie in the field ofminiaturized biochemical analysis systems and the application of suchsystems to clinical diagnostics.

Andreas Manz obtained his Ph.D. from the Swiss Federal Institute ofTechnology (ETH) Zurich, Switzerland, with Professor W. Simon. Histhesis dealt with the use of microelectrodes as detectors for picoliter-sizevolumes. He spent one year at Hitachi Central Research Lab in Tokyo,Japan, as a postdoctoral fellow and produced a liquid chromatographycolumn on a chip. At Ciba-Geigy, Basel, Switzerland, he developed theconcept of Miniaturized Total Analysis Systems (µTAS) and built up aresearch team on chip-based analytical instrumentation during 1988-1995. Since joining Imperial College, he has become the SmithKlineBeecham professor for analytical chemistry. His research interests includefluid handling and detection principles for chemical analysis, bioassays,and synthesis using microfabricated devices.


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